Book Review: Histopathology of Preclinical Toxicity Studies, Fourth Edition: Interpretation and Relevance in Drug Safety Evaluation

There are several books on the subjects of rodent pathology, toxicologic pathology, and toxicology and several veterinary and toxicologic pathology journals but nothing like this fourth edition of Peter Greaves’s treatise. It reads like a Greaves Tox Path Wiki or perhaps a Greavipedia on preclinical histopathology and toxicology. His progressive editions since 1991 have increased in thickness and weight, adding more information and thousands of references. A Kindle edition is available with links to references in the reference lists. His experience as a physician pathologist working on drug research and development, animal toxicity, and carcinogenicity studies is clearly demonstrated in this comprehensive text. Most animal lesions are discussed in the context of human toxicity or possible human toxicity. The book is organized by organ systems, including integumentary, mammary gland, hematopoietic and lymphatic, musculoskeletal, respiratory tract, cardiovascular, digestive (the longest at 106 pages), liver and pancreas, urinary tract, male genital tract, female genital tract, endocrine glands and nervous system, and special sense organs. Each chapter is loosely organized into the system’s anatomical components, normal morphology and physiology, nonneoplastic lesions, and neoplasia. In each chapter, there may be sections on drug-induced lesions in humans and animals, specific important lesions, controversial issues, and safety assessment. The discussion of comparative aspects of drug toxicity in humans and animals, lesions, and interpretation is extremely helpful for the pathologist. Not only are specific lesions discussed, but so are their importance in toxicity studies. In the liver chapter, these topics include enzyme inducers, liver weight changes, peroxisomal proliferation, drug-induced inflammation, and safety assessment of specific lesions. Many of these topics are well covered, and I usually agreed with Dr. Greaves’s interpretations. Each chapter has numerous references (hundreds per chapter), which are all referenced in the text. The liver chapter has 693 references, while the digestive system chapter has 694 references. The book lacks a few features that would be of great benefit, but then it would be much larger in size. The book lacks consideration of some chemicals that are not drugs but includes the important organ-specific chemicals. The book has few histopathology figures, but they are mostly very good and in color, except for electron micrographs. The figures tend to be of the classic lesions discussed. If you have the third edition, you might not want to buy this fourth edition. There are pages added, but this is not an extensive revised edition. If you do not have the third edition, this fourth edition can be extremely helpful if you are a veterinary or medical pathologist working with research and development and safety assessment of chemicals, particularly drugs. I highly recommend it for that audience and for toxicologists, other scientists, and regulators working with drug and other chemical safety. It is a must-have reference book in this field.

tion." Some of the opinions of Dr. K. on this subject have been already laid before our readers, in several communications and replies to opponents in former Numbers of our Journal; which he has here republished in an Appendix. This part, which occupies rather more than half the volume, contains also a considerable number of letters, written by other practitioners, some of which are original communications to Dr. K. and some have been published in the Journal.
Those opinions on which Dr. K. appears to lay most stress, may be collected from the following passages, extracted from his recapitulation, " The earliest records of medicine attest the existence of gouty inflammation ; and it has been uniformly considered, rather as a, remedial, than a morbid affection. " This erroneous opinion of its nature, and healthful influence, has survived the correction which enlightened reason afforded to the small-pox, the plague, and other forms of inflammatory diseases, in which stimulant treatment, and inviting and protracting ihe distemper on the surface, were also adjudged to be the only safe and efficient means of cure; but which unprejudiced Observation ultimately proved to be fatally hurtful, and that the very reverse was the most salutary that could be adopted. " The nature of gout is purely inflammatory, and possesses , no peculiar or specific properties to distinguish it from common inflammation, but what are referable to the structure or organization of the affected parts. " The seat of the gout is exclusively in the ligamentous and tendinous fabric; the texture of which, when  all that is peculiar or characteristic of gout. This fabric thcro tore is necessary lo the constitution ot what is called gouty inflammation, which evinces that it cannot occur on anv ot the visceral or vital organs, as these possess nothing of the ligamen-/ tons or tendinous structure* " The several appellations of gout, rheumatism, and sprain,. are only nominally different; they, in fact, describe identity of affection. Any external variation which may present in the degree and progress of the disorder does not alter the fundamental sameness of the disease, which consisting in an inflammatory irritation of' the ligamentous and tendinous structure, will exclusively remain such, however variously and capriciously denominated. The-origin of gout must necessarily be always local, as it can only arise in inflammatory affection of the ligaments and tendons, which are stationed almost exclusively at the joints, and are not co-extended with the system. The peculiar seat of gouty malady at once chains it to the ligamentous and tendinous structure, and gives an umleviating ^resemblance to its external character.
It necessarily originates in every instance in the same natural circumstances, and therefore invariably denotes its exist* once by the most unequivocal symptoms. " The diffusion, or propagation, of gout, from the affected joints, is governed by associative or sympathetic influence of mo?five power; but when arrested on any particular organ, as the brain, stomach, or bowels, it is not characteristic gout in those parts, but simple irritation ; the ligamentous and tendinous structure, necessary to gouty inflammation, being wanting in those vital organs.
Nor docs the local irritation of gout subside by sympathetic distribution, but in the proportion as the severity o? pain may have liar rasscd and exhausted thesystematic strength. The consequent general debility will then reduce the local inflamma-'tion, and occasion those painfully irregular or agitated motions-(usually termed spasm) over the system, which always endanger life, atid do often actually terminate in death. Gout, therefore, cannot be strictly repelled; and-when it subsides, and the system becomes affected, it is the consequence of extreme reduction of Constitutional strength, by protracted pain, and which might have been prevented by its seasonable relief. " The general health can suffer no other injury from gouty inflammation, than what is occasioned by the debilitating and distempering influence of durable irritation ; its early removal therefore renders the disease both mild and safe. " The general symptoms of gouty inflammation will depend on the temperamental, habitual, or morbid excitability of the system at large, or of any.particular organ. If equal health should ?pervade the frame, no serious impression need be dreaded; but if distempered excitability should have fixed its abode on any particular part, the accumulated weight, or concentered force of sympathetic irritation, may so heavily befall it, as to manifest * ; cry Dr. Klnglahc's Dissertation on Gout. 563 SVery degree of violence from transient to inflammatory excitement.
But whatever be the situation or extent of the morbid impression, its nature will be conformable to the structure and office of the affected part, and not to the character of gouty, or ligamentous and tendinous inflammation. " The protracted or natural duration of gout tends to produce irreparable local derangement on tliei part affected; and a state of -the system promptly susceptible of common Causes of morbid impression. The diseased joints will, by its long endurance, become contracted, aiid be farther distempered by altered structure, by calcareous or osseous, and other vitiated secretions J while tli6 general motive powers of thd system will be tremblingly alive to every occurring irritation. This deep and complicated mischief is only to be obviated by an early and radical removal of tlie disease. * Dr. Rote lei/s Scholtc Medicinet.
tion, is necessary, and by breaking the general strength may prove hurtful.
" The convalescence of gout will require the same attention to ?further and confirm its progress, as is necessary in that of other violent diseases.
A well-conducted plan of nutriment should be regarded as of the first importance in expediting and ensuring perfect recovery. Local friction also, and even topical warm bathing, would be advisable, if an unyielding sense of either torpor or coldness should prevail on the affected part. " Should a relapse actually occur, it should be treated as the original attack, with such adaptations as the circumstances of aggravated or diminished violence may require. " Gouty ailment may be cither obviated, or arrested in its formipg stage, so as to prevent its developement, by resisting the earliest approach of excessive temperature, either generally or locally, by topical cold, aqueous dilution, abstemious diet, cool apartments, avoidance of' costiveness, and every other source of morbid excitement, whether universal or partial." Improvements in medicine are made more slowly than in other sciences, bccause they are opposed by self interest and prejudice.
It becomes necessary therefore, from time to timd, to recall the attention of the profession to the errors and prejudices of former practitioners. This appears to have been Dr." lv's view in his present work; and there is no doubt that he will have many admirers and many opponents, so that the cause of science cannot fail to be promoted. Ayter the history and chronology of medicine down to the 19th century, Dr. R, addresses a short admonition to students, respecting the best mode of acquiring a" correct knowledge of the different branches of the science.
The Sccond Part, which may be considered as the principal one, and which occupies 104 pages of letter-press, besides the numerous plates, is devoted to the several branches of anatomy. Novelty/ or originality, is not to be expected on these subjects; judgment in selecting and arranging, perspicuity in explaining, and a happy illustration by good plates, are all that can be expected ; and in these, Dr. Pc. has not been defective. We discover in every part ot his work a great solicitude to consult the memory of the student ; and in order to do this, he disposes his subjects in a tabular form, when it can be done conveniently, and indulges in frequent repetitions, for the sake of placing the facts in various points of view, or recapitulating what is most necessary to be,remembered. An instance of this kind occurs in the beginning of the Third Part, 'where we find a Compendium or Abridgment of the Second Part. This is followed by an abridged Physiology, Pathology, and Symtomatology. The work is concluded by an account of the Man lebonc Infirmary, considered as a School of Medicine. As the author of this correct and useful work understood his own views and objects in publishing it better than any other person, we prefer his account of them to any we could give.
? " M-dicine, like all other arts, ha? its distinct family of terms " and idioms, conveying meanings peculiar and appropriate to its several branches ; and the very numerous sources from which these have been collected, have made it.not easy for its professors sufficiently to understand the language of their science. " I have therefore brought together such as usage has fixed, or learned men have adopted, and have contented myself with deducing them from their proper roots, determining their pronunciation, and simply defining them. " The unmeaning jargon nf Paracelsus and his followers I have purposely omitted, and have been solicitous to preserve those compound words used by the physicians of the Greek school, most or all of which are scattered about in the writings of succeeding ages. My authorities are chiefly derived from Blanchard, Castellus, Minshew, Schindler, and Golius. " That such a work is useful, will perhaps be more readily admitted'than that it has been usefully executed ; but he that has laboured long in attempting to remove the obstructions to science, is not willing to add despondence to his difficulties, and to believe that he hes laboured in vain." The modesty of the title, the correctness and perspicuity of the definitions or explanations of the words, almost disarm the hostility of criticism, if. we were ever disposed to indulge in it; but wo think no Lexicographer has a right or power to say, this is hereafter to be the language of these branches of science. Dr. Johnson, in his Dictionary, has purposely omitted many words whichought to have been retained, because he thought the English language better without them, or because he did not find such authorities for their use as he approved of. Dr. T. has imitated his example; and this is our only objection to the Glossary. Dr. Szecdiai\Ys Pharmacop&ia, use, and some varieties in the preparation of several of the suW stances used in'medicine. > The Preface begins by asserting the originality of the present compilation of prescriptions, for the greater number of which lie acknowledges his obligations to the experience of the successful practice of many of the London Hospitals. Indeed, in this poin^ of view, we apprehend that his work will be still more acceptable, to the French practitioners than to our own. The nomenclature of the chemical preparations is that which is now universally adopted by chemists ; in the vegetable kingdom the Linnrean is strictly followed. Among other alterations the term tcrebinthina is substituted for halsamum (for example, terebinthina copaiferac off* cinalis, instead of halsamum copaivae) and with prudent caution the name tinctura scdatha is made to supply the place of T, opii.
We pass over the author's severe censure on the (supposed) 11 i ppocratic practice, which renders the physician rather a calm spectator of the progress of disease than a vigorous opposer of its ravages, and proceed to a short view of the contents of the work itself.
The purely chemical part of Pharmacy, the preparation of the Seids, alkalies, neutral and earthy salts, begins the volume.. Among the less common of these articles of Materia Medica are "Wertendorfs radical vinegar, made by distilling acctite of soda-\vith sulphuric acid; the citric acid concentrated by frost and mixed with sugar to a dry lemonade ; the oxygenated muriatic acid; the phosphoric acid ; the sulphite of soda; and the citrates of all the alkalies. Whether many of these will prove permanent acquisitions of value to the Materia Medica appears very doubtful.
j Usus, aqua diluti: Ischuria renalis ; dysuria.?Concentrati cum luelle cxtcrmis: Aphtha;. ? Item ad varia pneparata pbarmaceutica. ? Forma vaporum ad putrida aeris effluvia corrigenda," After these follow the very important class of metallic salts. In the list of metals gold is still retained, very inconsistently in a book which so confidently assumes the merit, of excluding all antiquated absurdities; but though the name is retained, the single pre? paratiou of this metal is omitted. Under each metal the oxyds arc; first described, then the salts, and lastly the sulphurets. We shall only notice the rarer of these. M. Vauqueliu's convenient method of preparing the martial vthiops or black Qijjd of iron, is the following. Mix two parts of fine iron filings with one of the red oxi/d of iron (crxicus mart isJ, heat them in st covered crucible with a strong fire for an hour, and when cold reduce the coherent mass to a fine powder, which is the black oxyd. of making the same preparation by moistening iron filings with water and long exposure to air (originally Lemery's) is here introduced with trifling variation, and is ascribed to one Cavezalli, who, it would seem, has had the assurance to claim the invention.
In the important subject of mercurial preparations the author is already favourably known to the public, having formerly, in his Pharmacopoeia Syphilitica, exhibited a very full view of the various useful salts and oxyds of this metal. The black oxyd of mercury by tritvrej or by ammonia is not commonly met with in our shops. Its preparation is thus described : The emetic tartar, the author prepares with the white oxyd or powder of algaroth, but as this triple salt of antimony, potash, and tartarcous acid is found often to vary in its composition, the simple tartrite of antimony is recommended in preference. It is prepared merely by dissolving the white antimonial oxyde in tartarcous acid, and evaporating the solution to dryness.
To the metallic salts succeed the. Sulphurets, the only one of which worthy of remark, is the sulphuret <>f ammonia, made by passing sulphurated hydrogen gas through liquid caustic ammonia.
The gas may be extricated either by sulphuret of iron and muriatic, acid, or simply by heating the liquid sulphuret of pot-ash.
A few preparations under the title of Sapones follow. The intimate union of soap with the more powerful'gum-resins, has, with reason, been thought to improve their efficacy, and render them more soluble in the stomach They are also convenient to be exhibited in the form of pills. These are very intimately mixed by being together dissolved in alcohol, as the author prescribes, and the-solution evaporated to a pillular consistence.
The class of Injiammahilia includes charcoal, Sulphur, phosphorus, resins, oils, and animal fats. The purification of camphor by solution in alcohol and precipitation, is a needless refinement. The following is an imitation of the Indian volatile oil of camphor, so much extolled in rheumatic and gouty cases as an external application. " Mix half a pound of camphor with two pounds of dry pipe' clay, and distill in a glass retort with a very slow fire.
An acid liquor passes into the receiver,, together with a fine volatile oil, and a thick butyraceous oil concreted in the neck .of the retort. The volatile oil is to be separated and kept for use.
Among the aithers isgiven'Khiproth's Acetatcd-Ethereal TincJure of Iron. It is nine ounces of liquid acetite of .iron, mixed with ?three ounces of acetic ethereal spirit, the preparation of which is also given. A medicine of similar virtues is the nervine tincture, made with muriated iron and sulphuric ether. The whole section on ethers is valuable.
The article gaza (gasses) is much too scanty to give any real assistance to the preparer (oxygen excepted). > Ths composition of a few of the most celebrated of the natural or factitious mineral waters is added.
The second part of this Pharmacopoeia, is a large selection of formulas for the use of the practitioner, arranged according to the form of exhibition. -Of these, many are selected from, .various _? sources